Certain novel, 1-phenyl-3-[aminoalkylidene or di(loweralkyl)aminoalkylidene]-2(1H, 3H)-indolones, specifically substituted on phenyl with at least one alkyl, alkoxy, alkylthio, chloro, fluoro or trifluoromethyl group, are potent gabaergic agents, valuable in the treatment of schizophrenia per se, as well as in reversing or avoiding side effect of oral-facial dyskinesia (tardive dyskinesia), commonly seen in schizophrenic individuals under present or past treatment with a neuroleptic agent. The present invention encompasses these novel gabaergic agents, together with pharmaceutical compositions thereof, and use thereof in treating schizophrenia or reversing the side effects of a previously or concurrently administered neuroleptic agent. Most of these compounds also have valuable anxiolytic activity, as detailed below.
More broadly, the present invention encompasses variously substituted 1-phenyl-3-[aminoalkylidene-, lower alkylaminoalkylidene- and di(loweralkyl)aminoalkylidene]-2(1H,3H)-indolones (some of which are known compounds), novel 1-phenyl-3-(piperidino-, pyrrolidino-, morpholino- or imidazolo- alkylidene)-2(1H, 3H)-indolones and novel 1-phenyl-3-(2-pyrrolidinylidene, 2piperidinylidene, or 2-perhydroazepinylidene, optionally substituted on nitrogen with lower alkyl, phenyl or benzyl)-2(1H,3H)-indolones. These three classes of compounds are anxiolytic agents, valuable in the treatment of hyperanxious individuals. The present invention is thus also directed to the above two novel classes of compounds and pharmaceutical compositions thereof, and to the use of all three classes of compounds in the treatment of anxiety in hyperanxious individuals.
Belgian Patent No. 849,626 broadly discloses compounds of the formula ##STR1## which include m as 1, 2 or 3 and R.sup.a and R.sup.b each as H, OH, lower alkyl, lower alkoxy, F, Cl, Br, NO.sub.2, NH.sub.2 or C.sub.6 H.sub.5 CH.sub.2.
These compounds are not disclosed as having pharmaceutical utility per se, but rather are indicated to be chemical intermediates. The only compounds of this class isolated and characterized are the two compounds wherein R.sup.a =H and R.sup.b = 3-methoxy; and wherein R.sup.a =R.sup.b= H. The latter compound, like at least two dozen other compounds of this class, does not possess MPA (3mercaptopropionic acid) induced convulsion inhibitory activity ("gabaergic" activity). However, from among the many thousands of possible compounds defined by the Belgian patent, we have surprisingly found that a few, defined by the formula (I) below have gabaergic activity and so are useful in the treatment of schizophrenic individuals.